It is known in the pharmaceutical field that many drugs and classes of drugs exhibit poor or modest shelf stability. For example, a number of solid drug formulations experience such instability that after relatively short periods of time, significant portions of the active materials in the drug have been chemically transformed into other compounds. While such compounds are often relatively benign, occasionally the degradation product or products can either actually comprise an antagonist for the drug or give rise to adverse side effects. In any event, the diminution of desired, active ingredient in such drug formulations is of obvious, deleterious effect, making therapy with such drugs less certain. Accordingly, there is a long-felt need for drug formulations and for unit dosage forms of drugs which experience diminished degradation when compared to typical formulations.
Among the drug classes which are known to be liable to moisture-induced (e.g., hydrolytic) degradation and diminished shelf stability are the thyroid hormones. Thyroid hormones are suitable for therapeutic application in the treatment of hormone disorders. Particularly useful are thyroid hormones of natural or synthetic origin which bear about two or four iodine atoms. Examples of such thyroid hormones are levothyroxine, liothyronin, dextrothyroxine, triiodoacetic acid, thyroglobulin, diiodotyrosine, and analogs and salts thereof.
Levothyroxine is the levo isomer of thyroxine, an active physiological thyroid hormone obtained from the thyroid gland of animals or prepared synthetically. Clinically, levothyroxine is prescribed in thyroid replacement therapy for reduced or absent thyroid function of any etiology, including conditions such as myxedema, cretinism and obesity. Levothyroxine sodium, the sodium salt of levothyroxine, is the preferred form of administration of levothyroxine and is expressed by the chemical formula C15H10I4NaO4·xH2O. It is well known that the stability of levothyroxine is poor it is hygroscopic and degrades rapidly under conditions of high humidity or in the presence of other moisture sources. Levothyroxine also rapidly degrades in the presence of light, under conditions of high temperature, or in the presence of other pharmaceutical excipients, including carbohydrates such as, for example, lactose, sucrose, dextrose and starch, and certain dyes. Accordingly commercially available levothyroxine sodium tablet formulations exhibit a short shelf life.
Thyroid hormones are used therapeutically for thyroid diseases of various origins, including hypothyroidism, hypothyrosis, iodine deficiency and other related secondary diseases. Thyroid hormones are also used prophylactically. Thyroid hormones are used as medicaments and are extremely susceptible to temperature, humidity and oxidation. They are also prone to decomposition by various reaction mechanisms. Additionally, they react with many pharmaceutical excipients which makes it difficult to prepare pharmaceutical formulations containing thyroid hormones which remain effective for a sufficient period of time under regular storage conditions.
Significant efforts have been directed to the development of stable pharmaceutical formulations containing thyroid hormones for use as therapeutic agents. U.S. Pat. No. 5,225,204 (Jul. 6, 1993) is directed to a dosage form containing levothyroxine sodium which includes a stable complex of levothyroxine sodium and a cellulose compound, polyvinylpyrrolidone or a Poloxamer wherein the complex is adsorbed on the surface of a cellulose compound carrier.
U.S. Pat. No. 5,635,209 (Jun. 3, 1997) discloses a medication consisting of the combination of levothyroxine sodium with potassium iodide. This patent further discloses methods for making medication containing levothyroxine sodium comprising combining together levothyroxine mixed with a carrier, potassium iodide mixed with a carrier, a disintegrant, and a lubricant.
U.S. Pat. No. 5,955,105 (Sep. 21, 1999) describes a stable, dosage form pharmaceutical preparation, suitable for the treatment of thyroid disorders, comprising a thyroxine drug, a water soluble glucose polymer, and a partially soluble or insoluble cellulose polymer. This patent also discloses a stable pharmaceutical preparation comprising a thyroxine drug, a water soluble polysaccharide and a partially soluble or insoluble cellulose polymer. This patent further describes a stable pharmaceutical preparation comprising sodium levothyroxine, maltodextrin and microcrystalline cellulose.
U.S. Pat. No. 5,958,978 (Sep. 28, 1999) is directed to stable medicaments containing thyroid hormones wherein the medicament contains sodium thiosulfate as the stabilizing component. This patent also discloses methods for the preparation of stable medicaments comprising adding sodium thiosulfate in a dissolved state to a matrix mixture containing thyroid hormones.
In view of the extreme instability of thyroid hormones, such as levothyroxine, in the presence of moisture, light and heat, there is a long-standing need for stable formulations of thyroid hormones and methods of making such formulations. It is desirable to develop stable thyroid hormone-containing formulations which demonstrate a long enough shelf life for use as therapeutic agents. Also needed are methods for preparing such formulations wherein degradation of the thyroid hormones in the formulations is greatly reduced, thereby providing stable pharmaceutical formulations containing thyroid hormones for use as therapeutic agents in the treatment of disorders associated with reduction or absence of thyroid hormone production
Accordingly, it is a principal object of the present invention to provide unit dosage forms of solid drug formulations having a reduced tendency to degrade over time when compared with traditional formulations of such drugs. A further object of the invention is to provide methods of therapy comprising administering to a patient in need of a drug dosage form in accordance with the invention having such diminished tendency to degrade. Another object of the invention is to permit the U.S. and international registration and permission to market certain drug formulations which, absent the stabilization of the present invention, would not be registerable due to an unacceptably high rate of degradation. Other objects will become apparent from a review of the present specification and appended claims.